The invention relates generally to pharmaceutical formulations formulated for continuous delivery.
Erythropoietin (EPO) is a pleiotropic glycoprotein hormone produced primarily by the kidney. EPO stimulates the bone marrow to produce red blood cells and exerts tissue protective effects, e.g., neuroprotection, outside the bone marrow. EPO exerts its biological effect by binding to its cell surface receptor. EPO receptor agonists (ERAs) are a class of recombinant molecules that can activate EPO receptors. The recombinant molecules in the ERA class may or may not contain sequence homology to native human EPO (hEPO). Examples of products in the ERA class containing sequence homology to native hEPO are shown in Table 1 below.
TABLE 1Homology of AminoRecombinantAcid sequence to humanProduct NameMoleculeerythropoietinPROCRIT ®/EPOGEN ®Epoetin alfa100%EPREX ®/ERYPO ®Epoetin alfa100%NeoRecormon ®Epoetin beta100%ARANESP ®Darbepoetin alfa 97%
ERA products have been indicated for treatment of anemia due to chronic renal failure, anemia associated with cancer chemotherapy and surgery, and anemia secondary to AZT treatment of AIDS. ERA products currently on the market are administered to patients by subcutaneous or intramuscular injection thrice a week (EPREX®, ERYPO®, and PROCRIT®) or once a week (ARANESP®). Several ERA products currently on the market are liquid, are required to be stored at 2 to 8° C., and are unstable at room and elevated temperatures. ERAs are susceptible to aggregation, which can lead to reduced potency of the drug and may induce unwanted side effects. Adverse side effects associated with current administration of ERAs include, but are not limited to, thrombotic events, infection, hypertension, myalgia, and headache.
The therapeutic effects associated with administration of ERAs may be increased if ERAs could be delivered continuously in a low dose using, for example, implantable delivery devices such as osmotic, mechanical, or electromechanical pump implants. Use of implantable delivery devices generally assures patient compliance since implantable devices are not easily tampered with by the patient and can be designed to provide therapeutic doses of drug over period of weeks, months, or even years without patient input. With one insertion of the device, rather than injections every few days, there is reduced site irritation, fewer occupational hazards for patients and practitioners, reduced waste disposal hazards, improved cost effectiveness through decreased costs of equipment for repeated injections, and increased efficacy when compared to injections that require multiple administrations over relatively short time intervals.
In order to deliver ERAs from an implantable delivery device at a controlled rate over a prolonged period, ERAs must be contained within formulations that maintain their stability at elevated temperature, e.g., 37° C. or higher, over the operational life of the device, and the formulation must be in flowable form.